Benzodiazepinones and processes



United States Patent "Ce:

Patented Feb. 11, 1934- More particularly, the formulas of therespective benzo- 3121076 diazepinones can be set forth as follows:BENZODIAZEPENONE AND PRGQESSES (11) R; 0 Oscar Keller, Ciiiton, NorbertSteiger, Nntiey, and Lee I Henrylr Sternhach, Upper Mentclair, Ni,assign-01's to N C Hofimann-La Roche 1212., Nutiey, N51, a corporationR5 of New Eersey j: I GEE-R1 No Drawing. Filed Mar. 21, 1962, Ser. No.131,444 Claims priority, application Switzerland Dec. 2, was e=N 13Claims. (1. 266-4393 i This invention relates to substitutedbenzodiazepine s compounds which have been found to possess valuabletherapeutic properties. The invention also deals With intermediates forsaid compounds and methods or" mak- (III) R1 0 ing said compounds. Thebenzodiazepine compounds of this invention all contain a phenylsubstituent in the fi-position. Furthermore, either on the 5-positionphenyl R5 substituent or on the fused benzene ring all the benzo- 4diazepine compounds of the invention contain a nitrogen containingsubstituent. More specifically, the benzo- A l diazepine compounds ofthis invention are those chosen K from the group consisting of nitrogencontaining-substit- R3 uent substituted5-phenyl-2-amino-3H-l,4-benzodiazepine V 4 oxides, 5 phenyl 3H 1,4benzodiazepin 2(1H)- ones, and 5-phenyl-3H-1,4-benzodiazepin-2(1H)-one4- oxides.

Thus, certain compounds of the invention are selected from the roupconsisting of compounds of the formula As used in this disclosure, theterm lower alkyl includes saturated branched chain or straight chainaliphatic hydrocarbon groups such as ethyl, methyl, propyl, isopropyl,n-butyl, iso-butyl, t-butyl, amyl and the like.

Q0 The term halogen includes all four halogens, i.e. chlo- (1) f rine,bromine, iodine and fluorine. The lower acylamino N groups representedby R and R are those in which the R acyl radicals are derived from lowerfatty (alkanoic) 1 acids, forming groups such as aoetylamino, propionyl-/CHR2 amino and the like.

A Certain other compounds of the invention are selected from the groupconsisting of compounds of the formula wherein A represents a carbonnitrogen linkage which (IV) NH-Ra completes the 7-mernbered diazepinering and which 4O N=C/ is selected from the group consisting of O2N/CHR2 wherein R and R are selected from the group consistand ing ofhydrogen and lower alkyl, and R is selected from the group consisting ofhydrogen, halogen, lower alkyl, nitro, amino and lower acylamino.

The basic benzodiazepine compounds of this invention, i.e. the compoundsof Formula 1 above (which is inclusive of the compounds of Formulas IIand III above) and the compounds of Formula V above, form acid additionsalts. Since these compounds are valuable therapeutic agents,medicinally acceptable acid addition salts R R and R are each selectedfrom the group consistformed from pharmaceutically acceptable acids areprebd l! ing of hydrogen and lower alkyl; and R and R are ferred. Thesebasic compounds of Formulas I through each selected from the groupconsisting of hydrogen, IV above form pharmaceutically acceptable acidaddihalogen, lower alkyl, nitro, amino, and lower acyltion salts withboth organic and inorganic acids, such amino; at least one of R and Rbeingta nitrogen conas hydrochloric acid, nitric acid, hydrobromic acid,p-

taining group. toluene sulfonic acid, citric acid, maleic acid, succinicacid, mandelic acid, acetic acid, sulfuric acid, phosphoric acid,tartaric acid, and the like.

The compounds of this invention are derived from substitutedZ-aminobenzophenones. Several synthetic routes can be employed.

According to one method, a substituted Z-aminobenzophenone, such as5-nitro-2-aminobenzophenone, S-nitro- 2-methylaminobenzophenone, and thelike is reacted with an a-amino acid or an ester thereof conforming tothe formula wherein R is selected from the group consisting of loweralkyl and hydrogen and R is selected from the group consisting of loweralkyl and hydrogen.

For example, glycine and lower alkyl glycine esters can be used. Ringclosure occurs and a benzodiazepinone conforming to Formula III above isobtained wherein R is hydrogen and R R R and R correspond to thesubstituents on the Z-aminobenzophenones used as starting material. Theuse of longer chain a-amino acid answering to the Formula V abovewherein R is lower alkyl, e.g. alanine, results in a compound of FormulaIII wherein R is a lower alkyl group, i.e. a benzodiazepinone containinga lower alkyl substituent in the 3-position.

The reaction of the 2-aminobenzophenone and Ot-al'lllnO acid ispreferably effected in a solvent such as pyridine, dimethylformamide orthe like. It is also preferable to utilize one of the materials presentin the form of a salt of a strong organic or inorganic acid, eg glycinehydrochloride, glycine ethyl ester hydrochloride, alanine hydrochloride,pyridine hydrochloride, or the like.

According to an alternate method, the substituted 2- a'minobenzophenonecan be haloacylated, such as with bromoacetyl bromide, a-bromopropionylbromide, chloroacetyl chloride, or the like, toyield a 2-(a-halo-loweralkanoylamino)-benzophenone of the formula v1) R1 R2 I l NOOOI-IX Theresultant haloacylated-Z-aminobenzophenone can then be treated withammonia. This treatment with ammonia effects ring closure to obtain abenzodiazepinone conforming to Formula III above. It is most convenientfrom a viewpoint of operating economically and ease of handling to usealcoholic ammonia; however, other ammonia solutions can be used as isreadily apparent to those skilled in the art.

Benzodiazepinones conforming to Formula 111 above can also be preparedby cyclizing a 2-(a-amino-lower alkanoylamino) -benzophenone. These2-(et-amino-lower alkanoylamino)-benzophenones, their production, andtheir cyclization are not a part of this invention but are disclosedherewith in order that the present disclosure may be complete.

Compounds corresponding to Formula II above can be prepared by treatinga Z-halomethyl-4-phenyl-quinazoline 3-oxide of the formula with alkalihydroxides, such as sodium hydroxide, potassium hydroxide or the like.

Compounds of Formula IV above can be prepared from compounds of FormulaVII by reacting said compounds of Formula Vii with ammonia or with aprimary amine whereby the 6-membered heterocyclic ring of thequinazoline is enlarged to the 7-membered heterocyclic ring of thebenzodiazepine structure. 7

Compounds corresponding to Formulas I through IV above which contain anitro group on either the fused benzene ring or on the 5-position phenylring can be converted to the corresponding amino compound by reducingthe nitro group, for example,'catalytically in the presence of Raneynickel. A lower alkanoyl group can be attached to the amino group byreacting with a lower alkanoic acid anhydride, such as acetic anhydride.

The compounds corresponding to Formulas I through III above wherein R ishydrogen can be alkylated in the 1-position, for example by forming thesodio derivative with a sodium alcoholate such as sodium methoxide intoluene and then reacting the sodio derivative with a dialkyl sulfate oran alkyl halide in an inert solvent, for example a hydrocarbon ordimethy-lformamide.

it is also possible, as a further alternative, to first produce a2-amino-S-phenyl-3H-1,4-benzodiazepine 4- oxide; 5 phenyl 3H 1,4benzodiazepin '2(1H) one 4oxide; or 5-phenyl-3H-l,4-benzodiazepin-2(1H)-one derivative, either containing no substituent, or a group such as ahalogen or lower alkyl on the 5-position phenyl ring or lower alkyl onthe fused benzene ring, and then introduce a nitro group by nitrationwith nitric acid. One or two nitro groups may be introduced in thismanner. The 2 amino 5 phenyl 3H 1,4 benzodiazepiue 4- oxide; 5 phenyl 3H1,4 benzodiazepin 2(1H) one 4 oxide; or 5 phenyl 3H 1,4 benzodiazepin2(1H)- one compounds referred to above which do not contain a nitrogencontaining group are not a part of this invention but their preparationis disclosed herein in order that the present disclosure may becomplete.

The compounds corresponding to Formula VII above can be prepared byfirst acylating with an a-haloacylhalide or -anhydride compounds of theformula (VIII) NHR1 wherein R and R are each selected from the groupconsisting of hydrogen and lower alkyl; R and R are each selected fromthe group consisting of hydrogen,

3 halogen, lower alkyl, nitro, amino and lower acylamino; at least oneof R and R being a nitrogen containing group.

and then effecting ring closure to a compound of Formula VII viadehydration by acids, such as hydrogen chloride, concentrated sulfuricacid, and the like.

Certain of the Z-aminobenzophenones used as intermediates herein arenovel compounds and are included within the scope of the invention.

The compounds described above conforming to Formulas I through IV areuseful as muscle relaxants and anti-convulsants. They can be used forthe relief of tension and also in depressed states associated withtension. They can be administered by incorporating a therapeutic dosageof the compound, or a pharmacologically acceptable acid addition saltwhen formed, adjusted according to its nature and individualrequirements, in a conventional liquid or solid vehicle to provideelixirs, suspensions, tablets, capsules, powders or the like accordingto conventional pharmaceutical practice.

Certain of the intermediates which are used in the production of thecompounds of the formulas shown above .are novel. The method ofproducing such compounds is evident from the working examples whichdisclose their synthesis in detail. The following examples areillustrative and not limitative of the invention. All temperatures areexpressed in degrees Centigrade.

Example 1 Example 2 To a suspension or 10 g. (0.039 mole) of Z-amino-S-nitrobenzophenone oxirne in 100 cc. of acetic acid, warmed to 5060. 6cc. 0.08 mole) of chloroacetyl chloride was added in small portions,with stirring. The resulting brown solution was stirred at 50-6 for 3hours and then allowed to stand at room temperature overnight.

The reaction mixture was then saturated with hydrogen chloride andconcentrated in vacuo. The residue was dissolved in 200 cc. of warmmethylene chloride and was then cooled to 50 g. of crushed ice was addedto the reaction mixture, then 30 cc. 1 N NaOH dropwise until a pl-l of8-9 was reached. The mixture was transferred to a separatory funnel and150 cc. water were added. The organic phase was separated and dried overNa SO The methylene chloride solution was treated with activatedcharcoal, filtered, and evaporated to dryness in vacuo to give a yellowcrystalline residue. The crude product was purified by refluxing in amixture of 200 cc. acetone and 100 cc. methylene chloride with 15 g. ofactivated charcoal. 2 chlorornethyl 4 -phenyl-6-nitrcquinazoline-B-oxidecrystallized in yellow prisms on cooling of the filtered mixture.M.P.=205-207.

Example 3 6.0 g. (0.019 mole) of 2-c'nloromethyl-4-phenyl-6-nitroquinazoline 3-oxide was added in portions to 150 cc. of a 25%solution of rnethylamine in methanol at C. with cooling and stirring.After a few minutes, a yellow crystal ine substance started to separate.The reaction mixture was stirred at room temperature for 24 hours thenallowed to stand for another 24 hours. The yellow product was filteredoil, washed with a little methanol,

0 sucked dry, and crystallized in needles from ether-methanol giving7-nitro-2-rnethylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide, whichmelted at 26026l (dec.).

Example 4 6.3 g. (0.02 mol.) of2-chloroniethyl-4-phenyl-6-nitroquinazoline 3-oxide was suspended in 170cc. of 12% ethanolic ammonia. The dark reddish brown solution wasstirred for 24 hours at room temperature. The yellow prisms werefiltered oil, washed with ethanol, and sucked dry giving2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine 4-oxide. M.P. =243(dec.).

Example 5 A mixture of 16.8 g. or" Z-arninobenzophenone, 11.9 g. ofglycine ethyl ester hydrochloride and 200 cc. of pyridine was heated toreflux. After one hour, 20 cc. of pyridine was distilled oil. Thesolution was refluxed for 15 hours, then 11.9 g. of glycine ethyl esterhydrochloride was added and the refluxing was continued for anadditional 4 hours. The reaction mixture was concentrated in vacuo, thendiluted with ether and water. The reaction product,S-phenyl-SH-1,4-benzodiazepin-2(1H)-one, crystallized out, was filteredoff and then recrystallized from acetone in the form of colorlessrhombic prisms, MP. 182183.

The above mentioned 5-phenyl-3H-1,4-benzodiazepiu- 2(ll-i)-one is not apart or" this invention but its preparation is set forth above in orderthat this disclosure may be complete.

Example 6 48 g. (0.2 mol) or" S-phenyl-Bl-l-1,4-benzodiazepin-2(ll-i)-one was dissolved in 250 cc. or" concentrated sulfuric acid bystirring at 15 for /2 hour. The solution was then cooled to 0 and amixture of 9.1 cc. of fuming nitric acid (%-sp. gr.=1.50) and 11.8 cc.of concentrated sulfuric acid was added dropwise with stirring, keepingthe temperature of the reaction mixture between 5 and 0. Aftercompletion of the addition of the nitric acid-sulfuric acid mixture,stirring was continued for 1 hour and the reaction mixture was stored inthe refrigerator overnight.

The mixture was then added dropwise to 2 kg. of. crushed ice withstirriru. and cooling, keeping the temperature at 0. After 1 hour ofstirring in the cold, 640 cc. of concentrated ammonium hydroxide wasadded dropwise at 0 to pH 8. Stirring was continued for /2 hour and thecrude product was filtered oil, washed with a small amount of ice waterand sucked dry overnight. The crude product was suspended in a mixtureof cc. of methylene chloride and 1700 cc. of alcohol. 50 g. ofdecolorizing charcoal was added and the mixture was refluxed withstirring for 2 hours. After standing overnight at room temperature 15 g.of diatomaceous earth filter aid was added and the refluxing was resumedfor 1% hours. The mixture was filtered while hot. The clear, lightyellow filtrate was concentrated in vacuo on the steam bath withstirring to about 600 cc. The concentrate was stirred and cooled in icefor about 2 hours; the precipitated crystalline product was filteredoil, washed with some petroleum ether and sucked dry. The product,7-nitro-5- phenyl-Zvl-l-1,4-benzodiazepin-2(lH)-one, was recrystallizedfrom a mixture of 1000 cc. of alcohol and 50 cc. of methylene chlorideto obtain white prisms melting at 224225.

Example 7 12 g. (0.05 mol.) of S-phenyl-BH-1,4-benzodiazepin- 2(1H)-onewere dissolved in 65 cc. of concentrated sulfuric acid by stirring at10. The mixture was cooled to 0 and to it was added dropwise within 1hour, a solution of 5.3 g. of potassium nitrate in 30 cc. ofconcentrated sulfuric acid, keeping the reaction temperature below 25.The mixture was warmed to 50 for 2% hours and then added dropwise to 500g. of crushed ice with stirring and cooling to 0.

After standing overnight in the refrigerator, the reac tion mixture wasneutralized to pH 8 by the dropwise addition of 260 cc. of concentratedammonia at The crude material was filtered ofi, washed with some icewater, sucked dry, then crystallized from 125 cc. of boiling chlorobenzene. The product, 7nitro-5-phenyl-3H-l,4-benzodiazepin-2(1H)-one,was obtained in the form of light yellow prisms.

Example 8 A suspension of 5.6 g. (0.02 mol.) of 7-nitro-5-phenyl- 3H 1,4benzodiazep-in 2(lH)-one was reduced catalytically in a shakingautoclave using Raney nickel as catalyst at 265 lbs. hydrogen pressure.The hydrogen uptake was 100% of theory at 58. The catalyst was filteredoff and the cl ar, almost colorless filtrate was concentrated in vacuoto dryness. ne residue was crystallized from a mixture of 75 cc. ofacetonitrile and 25 cc. oi ethanol to obtain colorless prisms of7-amino-5- phenyl 'si-l-l,4-benzodiaZepin-2(lI-D-onc melting at 236-239.

Example 9 14 g. (0.056 mol.) of 7-amino-5-phenyl-3H-1,4-benzodiazepin-2(1H -one and 100 cc. of pyridine were stirred in a water bath at 40 for 1hour to obtain a fine suspension. 15 cc. of acetic anhydride was addeddropwise at to with slight cooling. A clear solution resulted which wasstirred at room temperature for 3 hours. After standing overnight atroom temperature, the slightly brownish reaction mixture was evaporatedto dryness in vacuo on the steam bath. Several portions of ethanol wereadded and distilled oil to remove traces of acetic anhydride. Theresidue was refluxed in 500 cc. of ethanol and filtered while hot. Afterconcentrating the filtrate to 200 cc., the pure product,7acetarnido-5-phenyl-3H- l,4-benzodiazepin-2(ll-l)-one, separated inwhite needles melting at 278-279.

Example 10 137 g. (1 mol.) of anthranilic acid was dissolved in 250 cc.dimethylformamide. The solution was cooled to 0 and 85 cc. (155 g.=1.3mol.) of thionyl chloride was added dropwise, keeping the temperature ofthe reaction mixture below 40. After allowing the mixture to cool toroom temperature, 750 cc. of acetone was added. It was then cooled to 0.The white Z-dimethylformarnidinoan uiamlic acid hydrochloride whichseparated was filtered oil, washed with 300 cc. of cold acetone andsucked dry, MP. 2152l7.

To a stirred suspension of 58 g. (0.25 mol.) or"2-dimethylformamidinoanthranilic acid hydrochloride in 750 cc. ofchlorobenzene was added in porti is 60 g. of phosphorus pentachloride.The mixture was heated on the steam bath for 2 hours and cooled in iceto 10. 135 g. or" aluminum chloride was added in 4 portions, keeping thetemperature of the reaction mixture below 10. After completi loride, the

on of the addition of the aluminum on mixture was heated on the steambath for 3 hours at 95.

The reaction mixture was cooled in ice and 400 g. of crushed ice wasadded in portions, keeping the temperature below 40. Next, 500 cc. of40% sodium hydroxide was added dropwise, again keeping the temperatureof the reaction mixture below 40. The pl-l at this point was about 11.Heating on the steam bath 95 for 4 hours followed, their cooling to 40.The mixture was transferred to a separatory funnel and the chlorobenzenephase was separated. The aqueous phase was extracted with three 100 cc.portions of chlorobeuzene and the combined chlorobenzene phases wereconcentrated in vacuo on the steam bath, yielding an oily residue. Theoil was refluxed with stirring in a mixture of 150 cc. of ethanol, 75cc. of water and 75 cc. of 10% sodium hydroxide for 24 hours. Thesolvents were distilled or: at atmospheric presure, the mixture was coand 500 cc. of water was added dropwise with stirring. After standing inthe refrigerator overnight, -the solid yellow product, 2-amino-4-chlorobenzophenone, was filtered off, sucked dry, dried in vacuo at roomtemperature over sodium hydroxide, then crysta -ized from 200 cc. of hotethanol in the form of yellow needles, MP. 9899.

A stirred mixture of 15.5 g. (0.067 mol.) of Z-amino-4-chlorobenzophenone, 35 cc. of pyridine and 15 g. (0.1 mol.) of glycineethyl ester hydrochloride was slowly distilled at 115120, with thepyridine being replaced dropwise to keep the volume unchanged. After 5hours, reaction mixture was concentrated to dryness in vacuo. Theresidue was heated on the steam bath with 50 cc. of benzene and 50 cc.of water. The extract was decanted and the residue was reextracted with50 cc. of benzene and 50 cc. of water. The insoluble brown precipitatewas filtered off and sucked dry. The crude product, 5 (p-chlo-rophenyl)SH-IA-benzodiazepin 2(1H)-one, was r crystallized twice from ethanol toobtain White plates melting at 262263.

The above mentioned S-(p-chlorophenyl)-3H-1,4- benzodiazepin-2(lH)-oneis not a part of this invention but its preparation is set forth abovein order that this disclosure may be complete.

33 g. (0.12 mol.) of 5-(pchloropheuyl)-3H-1,4-benzo (haze -2(ll-l)-onewere dissolved in 158 cc. of concentrated sulfuric acid by sti ring for/2 hour. The solution was cooled to 0 and a mixture of 6.1 cc. of fumingnitric acid (sp. gr.=1.50) and 7.3 cc. of concentrated sulfuric acid wasadded dropwise at -5 to 0. After an additional stirring period of 2hours in the cold, the reaction mixture was added dropwise to 750 g. ofcrushed ice with stirring at 0. The suspension was neutralized by thedropwise addition of 390 cc. of ammonium hydroxide at 0. The crudeyellow product was filtered oil, washed with 1 liter of ice water andsucked dry overnight.

Purification was accomplished by refluxing the crude material for 2hours in a mixture or" 5'00 cc. of ethanol, 500 cc. of methylenechloride, 35 g. of charcoal and 15 g. of filter aid. After filtration,the light yellow filtrate was concentrated in vacuo with stirring toabout 500 cc. Cooling of the concentrate in ice yielded the purecompound, 7-nitro-(5-p-chlorophenyl)-3H-1,4-benzodiazepin- 2(lH)-one, inwhite plates, which melted at 253-254".

Example 11 phenone in 30 cc. or diox-ane was treated with 10 cc. of

a 13% solution of ammonia in methanol. The solution was allowed to standat room temperature for 16 hours and then concentrated in vacuo at awater bath temperature or" 25. The residue was partitioned between 50cc. of ether and 50 cc. of 0.3 N hydrochloric acid. The other solutionwas again extracted with 50 cc. of 0.3 N hydrochloric acid and thecombined acid extracts were filtered and made alkaline with ammoniumhydroxide,

The precipitated product was filtered and dried in vacuo to give2-aminoacetarnido-S-nitrobenzophenone melting at 156-15 8 (dec.).Recrystallization from chloroformether gave light straw-colored needlesmelting at 16 6- 167 (dec).

The aqueous solution was neutralized with hydrochloric acid anddeposited, on standing, fawn-colored crystals of7-nitro-5-phenyl-3l-l-1,4-benzodiazepin-2( 11%) one.

Z-aminoacetamido-5-nitrobenzophenone was heated for 9 minutes at l65l87.The compound melted, frothed, and resolidified. The mass was dissolvedin chloroform and decolorized with charcoal. The chloroform solution wasconcentrated in vacuo and treated with ether to yield crystalline 7-nitro-5 -phenyl-3H-1,4-benzodiazepin-2 1H) one.

A solution of 2.42 g. (10 mmol.) of Z-amino-S-nitrobenzophenone and 4.2g. (30 mmol.) of glycerine ethyl ester hydrochloride in 75 cc. ofpyridine was refluxed for 16 hours. The pyridine was removed in vacuoand the residue was partitioned between 100 cc. of benzene and 100 cc.of water. The benzene solution was extracted with 80 cc. of 1 N sodiumhydroxide and the alkaline extract was neutralized with dilutehydrochloric acid. The precipitate was filtered oft, dried, thendissolved in chloroform and filtered from insoluble material. Thechloroform solution was concentrated in vacuo and the residuecrystallized from ether to yield crystalline 7-nitro- 5 -pheny1-3H-1,4-benzodiazepin-2- 1H) -one.

The Z-aminoacetamido-S-nitrobenzophenone compound referred to above isnot a part of this invention, but its preparation is set forth above inorder that this disclosure may be complete.

Example 13 A solution of 2.2 g. (9.1 mrnol.) of2-amino-4-nitrcbenzophenone in 150 cc. of benzene and 30 cc. of etherwas treated with 0.75 cc. (9.1 mmol.) of bromoacetyl bromide. Afterstanding for 5 minutes, the solution was washed with 150 cc. of waterand the procedure was repeated with further quantities of brornoacetylbromide and water until the yellow color of the solution haddisappeared. The organic layer was washed with water until the washingswere neutral and was then dried over sodium sulfate and concentrated invacuo. The residue was crystallized first from hexane-ether and thenhexanechloroform to give 2-brornoacetamido-4-nitrobenzophenone in theform of straw-colored melting at 120-121".

Example 14 A solution of 2.03 g. (5.6 mmol.) of2-bromoacetamido-4-nitrobenzophenone in a mixture of 100 cc. of etherand 50 cc. of a 10% solution of ammonia in methanol (wt/vol.) wasallowed to stand at room temperature for 18 hours. The solution was thenconcentrated to dryness in vacuo with a water bath temperature of 30.The residue was partitioned between ether and water and some insolublematerial was filtered off. The ether solution was dried over sodiumsulfate and concentrated in vacuo. The residue was extracted with hotbenzene to leave undissolved material melting at 243 (deo). The twobatches of insoluble material were combined and recrystallized fromethanol after treatment with charcoal to obtain colorless prisms of8-nitro-5-phenyl-3H-1,4- benzodiazepin-2(1H)-one melting at 252 (dec.).

Example A stirred solution of 75 g. of 2-amino-2'-nitrobenzophenone in700 ml. of hot concentrated hydrochloric acid was cooled to 0 and asolution of 21.5 g. of sodium nitriate in 50 ml. of water was added inthe course of 3 hours. The temperature of the suspension was kept at 27during the addition. The resulting clear solution was poured into astirred solution of 37 g. of cuprous chloride in 350 ml. of hydrochloricacid 1:1. The solid which had formed after a few minutes was filteredoff, washed with water and recrystallized from ethanol. Crystals of2-chloro-2'-nitrobenzophenone melting at 76-79 were obtained.

A solution of 20 g. of 2-chloro-2-nitrobenzophenone in 45 0 ml. ofethanol was hydrogenated at normal pressure and room temperature withRaney nickel. After uptake of ca. 6 liters of hydrogen the catalyst wasfiltered off, and the alcohol then removed in vacuo. The residue wasdistilled in a bulb tube at 0.4 mm. and t1 bath temperature 10 of150-165 giving a yellow oil. The oil was dissolved in alcohol, and onaddition of Water, needles of 2-amino- 2'-chlorobenzophenone melting at58-60 were obtained.

To a solution of 42 g. of 2-amino-2-chlorobenzophenone in 500 ml. ofbenzene, 19 ml. of bromoacetyl bromide was added dropwise. Afterrefluxing for 2 hours, the solution was cooled, washed with 2 N sodiumhydroxide and evaporated. The residue was recrystallized from methanolgiving crystals of 2-bromo-2-chlorobenzoyl)- acetanilide melting at119l21.

To a solution or" 14.5 g. of 2-brorno-2-(2-chlorobenzoyl)-acetanilide inml. of tetrahydrofuran, an excess of liquid ammonia (ca. ml.) was added.The ammonia was kept refluxing with a Dry-Ice condenser for 3 hoursafter which time the ammonia was allowed to evaporate and the solutionwas poured into water. Crystals of2-amino-2'-(Z-chlorobenzoyl)acetanilide were collected, which afterrecrystallization from ethanol melted at 162-164.

A solution of 3 g. of 2-amino-2'-(2-chlorobenzoyl)- acetanilide in 50ml. of pyridine was refluxed for 24- hours after which time the pyridinewas removed in vacuo. The residue was recrystallized from methanol and amixture of dichloromethane and ether giving crystals of 5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H) one melting at 212213.

The 5 Z-chlorophenyl) -3l-l-1,4-benzo diazepin-Z 1H) one mentioned aboveis not a part of this invention but intermediates therefor and itspreparation are set forth above in order that this disclosure may becomplete.

To solution of 13.5 g. of 5-(2-chlorophenyl)Gil-1,4benzodiazepin-2(1H)-one in 60 ml. of concentrated sulfuric acid, asolution of 5.5 g. of potassium nitrate in 20 ml. concentrated sulfuricacid was added dropwise. The solution then was heated in a bath at 4550for 2 /2 hours, cooled and poured on ice. After neutralizing withammonia, the formed precipitate was filtered oil and boiled withethanol. A small amount of white insoluble material was then filteredoil. The alcoholic solution on concentration yielded crystals of7-nitro-5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1l-l)-one which, afterrecrys tallization from dichloromethane, melted at 238 240".

Example 16 7 nitro 5 (2-chlorophenyl)-3H- l,4-benzodiazepin-2 (1H)-one(4.6 g.) was dissolved in 14.5 ml. of 1 N solution of sodium methoxidein methanol. After removing the solvent in vacuo the residue wasdissolved in 50 ml. of dimethylformamide and 10 ml. of methyl iodide wasadded. The solution was permitted to stand for 3 hours and the solventthen distilled off in vacuo. The residue was recrystallized from amixture of dichloromethane and ether yielding crystals ofl-methyl-S-(2-chlorophenyl)-7- nitro-3H-1,4-benzodiazepin-2(1H)-onemelting at 194- 195.

Example 17 A solution of 2.25 g. (9.3 mmol.) of2-amino-5-nitrobenzophenone in 150 cc. of benzene was treated with 2 cc.(18.6 mmol.) of a-bromopropionyl bromide. Dry air was blown through thesolution for one hour until the hydrogen bromide has been removed. Thesolution was then concentrated in vacuo and the residue was crystallizedfrom ether. The 2-(ix-brornopropionamido)-5-nitr0 benzophenone wasrecrystallized from a mixture of chloroform and hexane to obtain lightstraw-colored needles melting at l16117.

Example 18 A solution of 2.37 g. (6.3 mmol.) of2-(2-brornopropionarnido)-5nitrobenzophenone in 40 cc. of dioxane and 10cc. of a 13% solution of ammonia in methanol (wt./ vol.) was allowed tostand for 24 hours at room temperature. The solution was concentrated todryness in vacuo and the residue was partitioned between water and anether-methylene chloride mixture. The organic layer l l was dri d oversodium sulfate, treated with charcoal and then concentrated in vacuo.The residue was chromatographed on a 10 g. alumina column using first abenzenehexane eluant which removed the starting material and2-arnino-5-nitrooenzophenone. The column was then eluted with ether toobtain 7-nitro-5-phenyl-3-niethyl-1,4- benzodiazepin-2(1H)-one which wasisolated and melted at 219 221".

Example 19 5.6 g. (0.02 moi.) of7-nitro-5-phenyl-3li-1,4-benzodiazepin-2(1l-I)-one was suspended in 75cc. of methanol. 1.1 g. (0.022 mol.) of sodium methylate was added withstirring. The clear yellow-brown solution was concentrated to dryness invacuo giving the yellow sodio derivative. This sodio derivative wasdissolved in 7i; cc. of dimethylforrnarnide. 3.8 cc. (8.52 g.:().06moi.) of methyl iodide was added dropwise, the temperature rising to 30.The reaction mixture was cooled and stirred for 1 /2 hours. T he clearbrown solution was added to about 560 cc. of ice and water withstirring. The fine yellow precipitate was uttered oil, washed with icewater, suclre dry and dried in vacuo at 50 over sodium hydroxide. Thepure 1-metlryl7-nitro-5-pnenyl-3H-1,4-benzodiazepin- 2( ED-onecrystallized in needles from dilute ethanol and melted at 156157.

Hydrolysis of the compound obtained above in dilute hydrochloric acidgave Z-methylarnino-S-niirobenzopnenone which crystallized yellowneedles from acetonitrile and melted at 159-161".

Example 20 Example 21 A solution of 1 g. (2.75 rnrnol.) ofZ-bromoacetarnido- 3-nitrohenzophenone in 40 cc. of nitroinetha e wascooled in an ice oath and for 20 minutes saturated with ammonia. Afterstanding 3 hours the solution was concentrated in vacuo. The residue wasextracted from the inorganic salts with a mixture of ether and met ylenechloride. The solution was treated Wtih charcoal, filtered andconcentrated in vacuo. The residue was crystallized from a mixture tbenzene-hexane to give 9-nitro-5-phenyl-3l-l-1,4-benzodiazepin-2(ll-i)-one which, after recrystallization from ethanol,formed pale yellow needles at 144- Example 22 A solution of 4.5 g. (10.9nnnol.) of '2-(2'-oromopropionamido)-5-nitrobenzophenone in 109 cc. ofnitrornethane was saturated with ammonia and allowed to stand at roomtemperature for 70 hours. The solution was concentrated in vacuo at awater bath temperature of approxirn rely 20. The residue was dissolvedin a methyl ne clrlor et er nixture and the inorganic salts werefiltered off.

The filtrate was coneen 'ated in vacuo and the residue was crystallizedfrom a mixture of benzene and hexane.

The benzene-hexane mother liquor was chromatographed on a columnprepared with 130 g. of activated A m ure of benzene hexane (5 :2) wasused as cluan-t I a1 elation. On further elution with ether,7-nitro-5-phen l-3-n1ethyl-3il-1, i nrodiazepin- 2(1H) one was obtained.This was v asked with ether and mystallizcd from a benzene-hexane togive colorless needles rneling at 219-221".

Example 23 6.3 g. (0.02 mol.) of2-cl1loromethyl-4-phenyl-6-nitroquinazol-ine 3-oxide was suspended in amixture of 59 cc. ethanol and 2G- cc. acetone. 2-: cc. of normal NaOHwas added dropwise, the reaction mixture turning a dark brown color(pH:9-l0). The mixture was warmed to 40, then stirred at roomtemperature overnight. to reaction mixture was then adjusted to pH 5with dilute hydrochloric acid and concentrated in vacuo to dryness. Theresidue was refluxed with a rnixture of cc. ethanol and 30 cc. acetone.After filtration and concentration to 50 cc. a small amount of startingmaterial was filtered off and 7-nitro-5-phenyl 3H 1,4oenzodiazepin-2(1H)-one 4-oxide was obtained by precipitation with,etroleum ether. The pure product crystallized in yellow prisms fromethanol-petroleum ether and melted at 218220 (deo).

Example 24 need from alcohol giving crystals ofuromo-2-nitrobenzophenone melting at Example 25 To a solution of 62 g.of 2-aminc-2-nitrohenzophenone in 250 ml. of dichloromethane, 27 ml. ofbrornoacetyl bromide was added dropwise. The solution was red for 2hours, cooled, washed with sodium bicarbonate solution, and evaporatedto dryness. The residue was crystallized from benzene giving crystals of2-(2-hrornoacetarnido)-2-ni-rohenzophenone melting at 157-159".

To a solution or 20 g. of Z-(Z-bromoacetamido)-2- nitrohenzophenone in200 ml. of tetrahydrofuran, an excess of liquid ammonia (ca. 200 ml.)was added. The ammonia was kept refluxing for 4 hours using a Dry-icecondenser. Then the ammonia was allowed to evaporate slowly. After anover-all reaction time of 17 hours, the solution was concentrated invacuo and poured into a sodium bicarbonate solution. The solid materialwas filtered off and recrystallized from alcohol yielding crystals ofZ-arnino-Z-(Z-nitrobenzoyl)acetanilide melting at 157-159.

The above-mentioned 2-amino-2-(Z-nitrobenzoyi)acetanilide is not a partof this invention but its preparation is set forth above in order thatthis disclosure may be complete A solution of 5 g. of2an1ino-2'-(2-nitrobenzoyl)acetanilide in 50 of pyridine was refluxedfor 26 hours. After this time the pyridine was removed in vacuo and theresidue dissolved in a boilin mixture of 9 ml. of alcohol, 45 nil. ofconcentrated hydrochloric acid and 45 ml. of water. Decolorizing carbonwas added and after keeping the mixture on the steam bath for about 5-10minutes all insoluble material was filtered oil. The clear solution wascooled, neutralized with ammonia extracted with a ixture ofdichlorornethane and ether.

The organic phase was concentrated by evaporation and the residuerecrystallized from benzene. Crystals of 52-nitrophenyl)-3H-l,4-benzodiazepin-2( 1H) -one melting at 2-J6298 wereobtained.

Example 26 1 luv red into water, the resulting precipitate fili3 Aftercooling, the solution was poured on ice and neutralized with ammonia.The solid material which had formed was filtered and crystallized fromtetrahydrofuran yielding crystals or" 7-nitro-5 (Z-nitrophcnyl) 3H 1,4-benzodiazepin-2(1H)-one which, after drying at 70 in vacuo, melted at226-228.

Example 27 To a solution of 2.8 g. of 7-nitro-5-(Z-nitrophenyl)-3H-l,4-benzodiazepin-2(1H)-one in 20 ml. of methanol 8.5 ml. of a 1 Nsolution or" sodium methoxide in methanol was added. After removal ofthe methanol in vacuo the residue as dissolved in 40 ml. ofdimethylforrnamide and 8 ml. of methyl iodide was added. After standingfor 3 hours at room temperature the solvent was evaporated in vacuo, theresidue treated with ice water, and filtered. Crystallization from amixture of dichloromethane and methanol gave crystals of1-rnethyl-7-nitro (Z-nitrophenyl) 3H 1,4 benzodiazepin 2( lH)-onemelting at 209-212".

Example 28 A mixture of 12.3 g. of2-amino-4,5-dimethyl-4-nitrobenzophenone, 12.3 g. of hydroxylaminehydrochloride, 50 cc. of pyridine and 100 cc. of alcohol was refluxedfor 20 hours, then diluted with water and partly concentrated in vacuo.The precipitated crystalline reaction product,Z-amino-4,5-dirnethyl-4-nitrobenzophenone oxime was filtered off andcrystallized from methanol. It forms yellow prisms melting at 212-213".

Example 29 To a warm solution of 11.4 g. of 2-amino-4,5-dimethyl-4'-nitrobenzophenone oxirne in 175 cc. of acetic acid was added 9.04 -g.of chloroacetyl chloride. After 2 hours standing at room temperature themixture was saturated with hydrogen chloride, heated to 70 andconcentrated in vacuo. The residue was dissolved in methylene chlorideand washed with ice cold sodium carbonate solution. The organic solutionwas dried, concentrated to a small volume and diluted with petroleumether. The precipitated reaction product,6,7-dimethyl-2-chlorornethyl-4-(4'- nitrophenyl)-quinazoline 3-oxide,was filtered off and crystallized from acetone. After recrystallizationfrom acetone it forms yellow needles melting at 229-230.

Example 30 To a suspension of 6.8 g. of6,7-dimethyl-2-chloromethyl-4-(4-nitrophenyl)-quinazoline 3-oxide in 100cc. of ethanol was added 20 cc. of 1 N sodium hydroxide. The reactionmixture was heated to 40, diluted with 40 cc. of acetone and stirred atroom temperature for 17 hours. Some precipitated starting material wasfiltered off. The filtrate was concentrated in vacuo to a small volume,made alkaline with 20 cc. of 1 N sodium hydroxide and extracted withmethylene chloride. The alkaline aqueous part Was acidified with 40 cc.of 1 N hydrochloric acid and extracted with methylene chloride. Theorganic layer was dried, concentrated in vacuo to a small volume,treated wi h ether and yielded, after filtration, crude crystalline7,8-dimethyl-5-(4'-nitrophenyl)- 3H-1,4-benzodiazepin-2(1H)-one 4-oxide.The pure product, after crystallization from a mixture of methylenechloride and petroleum ether, forms slightly yellow plates melting at254-255".

Example 31 To 1.38 liters, of benzoyl chloride heated to 120 was added,with stirring and continued heating, 566 g. of 4-chloro-Z-methylani-line. At a temperature of 180, 800 g. of zincchloride was introduced. The temperature was then raised to 220-225 andmaintained there for 1.5 hours. The temperature was then decreased toabout 150 and 2 liters of 3 N hydrochloric acid was cautiously added.The biphasic mixture was refluxed for about 5 minutes. The hot aqueouslayer was decanted and the id residue washed once more with the sameamount of 3 N hydrochloric acid.

The residue was refluxed for 15 hours with a mixture of 660 cc. aceticacid, 375 cc. water and 700 cc. concentrated sulfuric acid. The reactionmixture was poured on ice and extracted with methylene chloride. Themethylene chloride extract was washed with water, dilute alkali, dilutehydrochloric acid, separated, dried and concentrated in vacuo todryness. The residue was crystallized from petroleum ether yieldingcrude product. Upon recrystallization from a mixture of ether andpetroleum ether, the purified 2-arnino-3-methyl-5-ch1orohenzophenoneformed yellow needles melting at 88.5-.

A mixture of 5.0 g. of activated charcoal (Norite-SG), mls. oftetrahydrofuran, 5.0 mls. of 5% pal'ladious chloride solution, 15.0 g.of powdered potassium acetate and 24.6 g. of2-amiuo-3-rnethy1-5-chlorobenzophenone was shaken in a closed vessel ina hydrogen atmosphere (2 atmospheres pressure) until 0.1 mole ofhydrogen was absorbed (5-6 hours). The :mixture was then filtered andthe yellow filtrate evaporated to a syrup in vacuo. The syrup wasdissolved in methylene chloride and the solution washed with 3 Nhydrochloric acid. The solvent layer was dried and evaporated in vacuo.The oily residue was crystallized from Skel-lysol-ve A to give purified2- amino-B-methylbenzophenone melting at 51-52.

To an ice cold solution of 27.6 g. of 2-amino-3-methylbenzophenone in200 cc. .benzene was added, in portions with stirring, 14 cc. ofbromoacetyl bromide and cc. of l N sodium hydroxide at such a rate as tokeep the mixture slightly acidic. The organic layer Was then separatedand washed with dilute alkali and water. The benzene solution was dried,concentrated in vacuo to a small volume, and diluted with ether andpetroleum ether. The precipitated crystals of 2-bro:moacetamido-3-methylbenzophenone melted at 117-118".

A solution of 18.2 g. of 2-bromoacetamido-3-methylbenzophenone in 300cc. of liquid ammonia was stirred at atmospheric pressure until theammonia had evaporated (about 5 hours). The residue was dissolved inbenzene and washed with water. The organic layer was dried andconcentrated in vacuo. The residual syrup was dissolved in pyridine,refluxed for 3 hours, concentrated in vacuo to dryness. The residue wascrystallized from a mixture of benzene and petroleum ether yielding 10.6g. of crude reaction product. The purified 9-methyl-5- phony-l 3H 1,4benzodiazepin 2(11-1) one was crystallized from a mixture of methylenechloride and petroleum ether. It formed colorless prisms melting at184-185.

The above-mentioned 9-*nethyl5-phenyl-3H-1,4-benzodiazepin-2'(lH)-one,its preparation and intermediates are not a part of this invention butare set forth above in order that this disclosure may be complete.

To a solution of 12.5 g. of crude 9-methyl-5-phenyl-3H-1,4-benzodiazepin-2-(1H)-one in 80 cc. of concentrated sulfuric acidwas added dropwise with stirring at 5-10 5.3 g. of potassium nitratedissolved in 30 cc. concen trated sulfuric acid. The mixture was stirredat room temperature for 2.5 hours then poured over ice and neutralizedwith ammonium hydroxide. The precipitated crude reaction product wasfiltered 01? and recrystallized from methylene chloride yielding crude9methyl-7-nitro- 5-phenyl-3H-1,4-benzodiazepin-2(lH)-one. Purified 9-methyl 7 nitro 5 phenyl 3H 1,4 benzodiazepin- 2(1H)-one was obtained bycrystallization from large amounts of ether and formed colorless needlesmelting at 202-204.

Example 32 To a solution of 32.7 g. of 4-methylanthrani-lic acid in 100cc. of dimethylforrnamide cooled to 10 is added dropwise 20 cc. ofthionyl chloride. The temperature rises to about 5. The mixture is thenstirred at room temperature for 3 hours, diluted with 600 cc. ofacetone, cooled to +5 and stirred for an additional 3 hours.

l The reaction product, N-(2-carboxy-5-methyl-phenyl)N,N'-dimethylformamide hydrochloride, is filtered oil, Washed with coolacetone and dried. After reciystallizzv tion from a mixture ofacetonitrile and alcohol containing a small amount of hydrogen chloride,the product forms crystals melting at l96-l98.

A mixture of 500 cc. of benzene, 46 of phosphorus pentachloride and 48.7or" N-(Z-carboxy-S-methylphenyl)-N,PY-dimethylformamide hydrochloride isrefiuxed and stirred for 1 hour and cooled to 25. 130 g. of aluminumchloride and 50 cc. of benzene is added and the mixture is refluxed forhours. 450 g. of ice is then added, the mixture is made alkaline with700 cc. of 40% sodium hydroxide solution and refluxed for 5 hours. Thebenzene layer is separated, concentrated, and the residue refluxed witha mixture of 200 cc. of ethanol and 200 cc. of sodium hydroxide for 12hours. The alcohol and most of the Water are removed in vacuo and, tothe residue, 250 cc. of water and 150 cc. of benzene are added. Thebenzene layer is separated and concentrated in vacuo yielding crudeZ-arninoi-methylbenzophenone. On treating with petroleum ether, a yellowcrystalline precipitate is formed which is filtered 05. It melts at6840".

A mixture of 21.8 g. of 2-amino-4-methylbenzophenone, 100 cc. ofpyridine, 1 cc. of piperidine, and g. of glycine ethyl esterhydrochloride is refluxed for 16 hours. The reaction mixture isconcentrated in vacuo and the residue is heated up with 150 cc. ofbenzene and 100 cc. of water. This mixture is then cooled to 10 andfiltered. The crude product, 8-methyl-5-phenyl-3H-l,4-benzodiazepin-2(lH)-one, remaining on the funnel is Washed with Waterand crystall'ued from a mixture of methanol and acetonitrile formingprisms melting at 255-256".

The above-mentioned 8-methyl-5-phenyl-3l-l-1,4-benzodiazepin-2(lll)-one,its preparation and intermediates are not a part of this invention butare set forth above in order that this disclosure may be complete.

To a solution of 6.4 g. of crude S-rnethyl-5-phenyl-3P-l,4-benzodiazepin-2(1H)-one in 100 cc. o5 concentrated sulfuric acid,are added at l0l5 2.7 g. of potassium nitrate. The mixture is stirredfor 30 minutes at room temperature, 90 minutes at and 75 minutes at Itis then poured on about 700 g. of ice and neutralized at 0 with about280 cc. of ammonia (30%). The reaction product,8-rnethyl-7-nitro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one, is filteredoff, washed with water, and recrystallized from chlorobenzene and thenfrom benzene. It forms colorless crystals melting at 2l8-2l9.

Example 33 A solution of l g. of 9-methyl-7-nitro-5-phenyl-3l-l-l,4-benzodiazepin-2(lH)-one in a mixture of 25 cc. ethanol and 25 cc. 3 Nhydrochloric acid was refluxed for 0.5 hour. The reaction productcrystallized out during the reaction and was filtered ofi" aftercooling. The pure 2- amino-S-methyl 5 nitrobenzophenone was crystallizedfrom ethanol and formed yellow needles melting at 204-205.

Example 34 A solution of 1.2 g. of S-methyl-7-nitro-5-phenyl-3H-l,4-benzodiazepin-2(ll-D-one in a mixture of 25 cc. ethanol and 25 cc. 3N hydrochloric acid was refluxed for 2 hours, then left at roomtemperature. The reaction product 2-a1nir1o-4-methyl-5-nitrobenzophenonecrystallized out and was filtered ed. The2-amino-4-methyl-5-nitrobenzophenone was crystallized from ether andformed yellow plates melting at l77 l78 Example 35 A mixture of 176 g.of ortho-fiuoro bcnzoyl chloride and 64- g. of para-chloroaniline wasstirred and heated to 180, at which temperature 87 g. of zinc chloridewas introduced, the temperature raised to 200205 and maintained therefor forty minute The golden colored melt was q enched by the carefuladdition of 500 ml. of 3 N hydrochloric acid and the resulting mixturerefluxed for five minutes. The acid solution was decanted and theprocess repeated three times to remove all orthoiluorobenzoic acid. Thegre granular residue was dissolved in 300 ml. of 75 percent (vol./vol.)sulphuric acid and refluxed for forty minutes to complete hydrolysis.The hot solution was poured over 1 kg. of ice and diluted to two literswith water. The organic material was extracted with four 300 ml.portions of methylene chloride, and the combined extracts subsequentlywashed with two 560 ml. portions or" 3 N hydrochloric acid to removetraces of para-chloroaniline, three 500 ml. portions of 5 N sodiumhydroxide solution to remove orthoiuoro'oenzoic acid, and finally two200 ml. portions of saturated brine solution. The combined methylenechloride extracts were dried over anhydrous sodium sulfate and thesolvent removed to give the crude 2-amino-5-chloro-2- iluorobenzophenonewhich upon recrystallization from methanol formed yellow needles meltingat 9495.

v0.0 g. of 2-amino-5-chloro-2-fluorobenzophenone in 00 cc. oftetrahydroiuran was hydrogenated at atmosieiic pressure in the presenceor" 10 g. of charcoal (Norite), 30.0 g. of potassium acetate and 2.5 cc.of a 20 percent palladous chloride solution (20 percent by weight ofpalladium). After an initiation period varying from ten minutes to anhour, hydrogen uptake was rapid and stopped completely after theabsorption of the theoretical amount. Filtration of the catalyst over aHyfio pad and removal of the solvent left a yellow crystalline residue.The crude mixture of ketone and potassium acetate was partitionedbetween methylene chloride (300 cc.) and water (1 1.). The layers wereseparated and the water layer washed with methylene chloride (3 X50cc.). The organic layers were combined, washed with 3 N sodium hydroxidesolution (2X50 cc.), water (3 X cc.), dried over anhydrous sodiumsulfate and filtered. The solvent was removed and the productrecrystallized from ethanol to give Z-amino-Z'-fluorobenzophenone asyellow prisms melting at 126428.

A solution of 21.5 g. of 2-amino-2'-fiuorobenzophenone in 500 cc. ofether was treated with 20 cc. of a 20 percent (v./v.) solution ofbromoacetyl bromide in ether. The mixture was shaken and allowed tostand for five minutes and then washed with Water (20 cc.). The processwas repeated five times. The final solution was washed thoroughly withwater (SXSGO cc.) and concentrated to 100 cc. The crystals were filteredand recrystallized from methanol to give 2-bromoacetarnido-2'-fluorobenzophenone as white needles melting at 117ll8.5.

A solution of 23.7 g. of 2-bromoacetamido-2-fiuorobenzophenone intctrahydroiuran cc.) was added to liquid ammonia (approximately 500cc.), and allowed to evaporate overnight. The residue was treated withwater (1 l.) and the crystals filtered off and refluxed in toluene (160cc.) for thirty minutes. The mixture was treated with decolorizingcarbon (Norite) and filtered over Hyllo. The solution was concentratedto a small volume (25 cc.) cooled, diluted with 20 cc. of ether andallowed to stand. The product was recrystallized from acetone/hexane togive S-(Z-fiuorohpenyl)-3H-l,4-benzodiazepin-2(lll)-one as white needlesmelting at l80-l8l.

23.8 g. of 5-(2-fluorophenyl)-3H-l,4-benzodiazepin- 2(lH)-one wasdissolved in 50 cc. of concentrated suluric acid at 0. To the resultingmixture the-re was then added dropwise with stirring a solution of 7.1g. of potassium nitrite in 20 cc. of concentrated sulfuric acid. Themixture was stirred for 2 /2 hours at 0 and then diluted with 380 g. ofice. The resul ing solution was made alkaline with concentrated ammoniumhydroxide solution, keeping the temperature at 0. The formed suspensionwas extracted thoroughly with methylene chloride (6X 100 cc.). Theorganic layers were combined, washed with saturated brine solution,dried over anhydrous sodium sulfate, and filtered. Removal of thesolvent yielded a brown gum which was taken up in a small amount ofmethylene chloride and filtered through a pad of grade I alumina. Thealumina was eluted with methylene chloride, the solvent removed, and theresidue crystallized from acetone/hexane to yield7-ni-tro-5-(2-fluorophenyl)- 3H-1,4-benzodiazepin-2('1H)-one as whiteneedles meltingat 2l0-211.

A solution of 11 g. of this product in a mixture of 150 ml. of ethanoland 100 ml. of 3 N hydrochloric acid was heated on a steam bath for 12hours. The mixture was diluted with .100 ml. of water and allowed tocool to room temperature. The crystalline product was filtered, washedwith water, dissolved in 200 m1. of methylene chloride, dried overanhydrous sodium sulfate, filtered, concentrated to -a small volume, anddiluted with ether, whereupon the product crystallized yielding2-amino-5- nitro-2-fluorobenzophenone as yellow needles melting at154-158.

20.2 g. of the above mentioned 7-nitro-5'-(2-fluorophenyl) -3H- 1,4-benzodiazepin-2( 1H) -one was dissolved in 60 cc. of N,N-dimethylformamide to which was then added 3.49 g. of a 50% suspension of sodiumhydride in heavy mineral oil. The mixture was allowed to stir for 15minutes in the cold, 11.2 g. of methyl iodide was added and the solutionwas stirred for a further 20 minutes. Solvent was removed under reducedpressure to give an oil which was partitioned between water andmethylene chloride 1 l./300 cc.), the water layer was extracted withmethylene chloride X200 cc.), the organic layers combined, washed withwater (2x100 cc.), 3 N hydrochloric acid (1X50 cc.), water (3x100 cc.),dried over anhydrous sodium sulfate and filtered. Removal of the solventgave an oil which was taken up in ether and liltered through a pad ofWoelm grade I alumina. The eluent was concentrated and the residue wascrystallized from methylene chloride/hexane yielding 1-methyl-7- nitro 5(2 fluorophenyl) 3H 1,4 benzodiazepin- 2(1H)-one as pale yellow needlesmelting at 166-167". A solution of 12.0 g. of this product in a mixtureof 150 ml. of ethanol and 100 ml. of 3 N hydrochloric acid was heated ona steam bath for 12. hours. The mixture was diluted with 100 ml. ofwater and allowed to cool at room temperature. The crystalline productwas filtered, washed with water (5x200 ml.). The ketone was dissolved in200 ml. of methylene chloride, dried over anhydrous sodium sulfate,filtered, concentrated to 50 ml. and diluted with 150 ml. of etheryielding 2-(N-methylamino)-5-nitro-2'-fluorobenzophenone as pale yellowneedles melting at 186-187".

A mixture of 5 g. of the above mentioned 7-nitro-5- 2-fluorophenyl-3H-'1,4-benzodiazepin-2( 1H) -one and 1 g. of Raney nickel washydrogenated to completion at atmospheric pressure and at roomtemperature. The reaction was slow but stopped after uptake of 0.0498mole of hydrogen. The catalyst was filtered off and the solventconcentrated to about 15 cc. The crystals obtained from the cooledsolution were filtered and crystallized from methanol, yielding7-amino-5-(2-fluoropl1enyl)-3H-l,4- benzodiazepin-2(lH)-one as yellowprisms melting at 264-266".

The above mentioned 5-(2-fluorophenyl)-3H-l,4 benzodiazepin-2(lH)-one,the method for its preparation and the intermediates therefor are not apart of the present invention, but such are discussed above in orderthat the present disclosure may be complete.

Example 36 To a solution of 5 g. of 7-nitro-5-(4-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one in 15 ml. of dimethylformamide, asolution of 0.402 g. of sodium in 4 ml. of methanol was added, and thenthe mixture was stirred for 30 minutes at room temperature. The solutionof the sodio derivative was cooled to --5 and 11.5 g. of methyl iodidewas *added thereto dropwise over ten minutes, keeping the temperaturebetween 3 and 0. Stirring was continued for ten minutes at 0 and then atroom temperature for one hour. The mixture was poured into 1 l. of waterand the product extracted with methylene chloride (3 X150 ml.). Theorganic extracts were combined, washed with water (3 X200 ml), driedover anhydrous sodium sulfate, and filtered over a small column ofalumina g., neutral, grade 1). The solvent upon evaporation gave an oil,which was crystallized from an acetone/hexane mixture yielding5-(4-chlorophenyl)-1- methyl-7-nitro-3H-l,4-benzodiazepin-2('lH)-one ascolorless rods, melting at 13l-l35.

A solution of 0.6 g. of 5-(4-chlorophenyl)-1-methyl-7-nitro-3H-1,4-benzodiazepin-2(lH)-one in a mixture of 70 ml. of ethanoland 45 ml. of 3 N hydrochloric acid was heated on a steam bath for 12hours. The mixture was diluted with 50 ml. of water and allowed to coolto room temperature. The crystalline product was filtered, washed withwater, dissolved in 100 ml. of methylene chloride; the solution wasdried over anhydrous sodium sulfate, filtered and concentrated todryness. The residue was crystallized from methanol, yieldingZ-(N-methylamino)-4'-ch1orobenzophenone as yellow needles melting at2075-208".

Example 37 A solution of 29.5 of 1-methyl-7-nitro-5-phenyl-3H-l,4-benzodiazepin-2(1H)-one in 500 ml. of ethanol was hydrogenated atroom temperature and atmospheric pressure for four hours in the presenceof 0.7 g. of wet Raney nickel. Filtration, followed by concentration ofthe fil trate, yielded crude product which upon recrystallization fromethanol gave 7-amino-1-methyl-5-phenyl-3H-1,4- benzodi-azepin-2(1H)-oneas yellow prisms melting. at 23 8-240".

Example 38 A solution of 10 g. of 7-nitro-5-( 2-chlorophenyl)-3H-1,4-benzodiazepin-2(lH)-one in l l. of ethanol was hydrogenatedovernight at room temperature and atmospheric pressure in the presenceof 0.6 g. of wet Raney nickel. Filtration and concentration of thefiltrate yielded 7 amino 5 ('2 chlorophenyl) 3H 1,4henzodiazepin-2(1H)-one as yellow needles which, upon recrystallizationfrom ethanol, melted at 230-232.

Example 39 I A solution of l g. of 7-nitro-5-(4-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one in a mixture of 25 ml. of 3 N hydrochloricacid and 25 ml. of ethanol was refluxed on the steambath for 35 minutes.The reaction mixture was cooled and the crude reaction product filteredoff. Recrystallization from ethanol yielded 2-amino-5-nitro-4'chlorobenzophenone as yellow needles melting at 196-7".

Example 40 A solution or" 2 g. of 7-nitro-5-(Z-nitrophenyl) -3H-1,4-benzodiazepin-2( 1H)-0ne in a mixture of 20 ml. of acetic acid and 30ml. of concentrated hydrochloric acid was refluxed for 17 hours. Thesolution was then cooled, poured on ice, neutralized with ammonia andextracted with ether. The ether solution was washed with water, driedand evaporated. The residue was recrystallized from ethanol yielding2-amino-2,5-dinitrobenzophenone as dark orange prisms which melted at199-202.

Example 41 A solution of 1 g. of S-(Z-chlorophenyl)-7-nitro-3H-l,4-benzodiazepin-2(lH)-one in a mixture of 25 ml. of ethanol and 25 ml.of 3 N hydrochloric acid was refluxed for 3 hours. After the main amountof ethanol was removed in vacuo the solution was cooled. The crystallineprecipitate was collected on a filter and recrystallized from ethanolyielding Z-amino-2'-chloro-5-nitrobenzophenone as yellow prisms meltingat 118120.

This application is a continuation-in-part of application Serial No.38,732, filed June 27, 1960, now abandoned; and application Serial No.104,227, filed April 20, 1961.

We claim:

1. A compound selected from the group consisting of compounds of theformula and their pharmaceutically acceptable acid addition salts;wherein A represents a carbon-nitrogen linkage which completes the7-membered diazepine ring and which is selected from the groupconsisting of and R R and R are selected from the group consisting ofhydrogen and lower alkyl; and R and R are selected from the groupconsisting of hydrogen, halogen, lower alkyl, nitro, amino, and loweralkanoylamino; at least one of R and R being a nitrogen containinggroup.

2. A compound of the formula l phenyl 3. A compound of the formula loweralkyl phenyl 4. A compound of the formula I monolialophenyl 2% 5. Acompound of the formula lower alkyl l monohalophenyl wherein Arepresents a carbon-nitrogen linkage which completes the 7-membereddiazepine ring and which is selected from the group consisting of and RR and R are selected from the group consisting of hydrogen and loweralkyl; and R and R are selected from the group consisting of hydrogen,halo gen, lower alkyl and nitro; at least one of R and R being nitrowhich comprises nitrating with nitric acid a compound of the formulawherein A represents a carbon-nitrogen linkage which 21 22 completes the7-membered diazepine ring and which R R and R have the same meaning asabove; is selected from the group consisting of and R is selected fromthe group consisting of hydrogen, halogen and lower alkyl.

C=N l 5 References Cited in the file of this patent R UNITED STATESPATENTS 2,893,992 Stembach July 7, 1959 OTHER REFERENCES and 10 Yale:Jour. of Med. and Pharm Chem, vol 1, No. 2

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA
 13. A PROCESS FOR THE PRODUCTION OF COMPOUNDS OF THE FORMULA